From crystallographic fragment screen to preclinical candidate: Open science discovery of SARS-CoV-2 antivirals
FEBS Open Bio
; 12:65, 2022.
Article
in English
| EMBASE | ID: covidwho-1976668
ABSTRACT
The development of novel, low cost and globally available antiviral therapeutics remains an essential goal for the current SARS-CoV-2 pandemic. Furthermore, future pandemics could be prevented with easily deployable broad-spectrum oral antivirals and open knowledge bases that de-risk and accelerate novel antiviral discovery and development. To identify starting points for the development of such therapeutics, the XChem team at Diamond Light Source, in collaboration with various international colleagues, performed large crystallographic fragment screens against 8 key SARS-CoV-2 protein targets including the Main protease1, the Nsp3 macrodomain2 and the helicase Nsp133. The expeditious collection and open dissemination of the data from these fragment screening campaigns was enabled by the well-established platform at Diamond Light Source and by the implementation of various experimental and computational tools. This work identified numerous starting points for the development of potent anti-viral therapeutics as exemplified by the COVID Moonshot - a fully open-science structure-enabled drug discovery campaign targeting the SARS-CoV-2 main protease. 4 By leveraging crowdsourced medicinal chemistry design, high throughput structural biology, machine learning and exascale molecular simulations, we discovered a novel chemical scaffold that is differentiated to current clinical candidates in terms of toxicity and pharmacokinetics liabilities, and developed it into orally-bioavailable inhibitors with clinical potential within 2 years. All compound designs, structural data, assay data and synthesized molecules have been shared rapidly and openly, creating a rich, IP-free knowledgebase for future anti-coronavirus drug discovery.
anticoronavirus agent; antivirus agent; coronavirus 3C protease; diamond; endogenous compound; conference abstract; controlled study; coronavirus disease 2019; crystallography; light; machine learning; medicinal chemistry; nonhuman; pharmacokinetics; preclinical study; Severe acute respiratory syndrome coronavirus 2; simulation
Full text:
Available
Collection:
Databases of international organizations
Database:
EMBASE
Language:
English
Journal:
FEBS Open Bio
Year:
2022
Document Type:
Article
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